Use of Lck inhibitors for treatment of immunologic diseases

ABSTRACT

The invention relates to a method of treating immunologic diseases or pathological conditions involving an immunologic component using certain Lck inhibitors already known as kinase inhibitors for therapy in oncology, optionally in combination with one or more other drugs selected from NSAIDs, steroids, DMARDs, immunsuppressives, biologic response modifiers and antinfectives, pharmaceutical compositions comprising said Lck inhibitors together with said other drugs, and the use of the Lck inhibitors for the manufacture of a pharmaceutical composition for the treatment of immunologic diseases or pathological conditions involving an immunologic component.

TECHNICAL FIELD OF THE INVENTION

[0001] This invention relates to a method for treating immunologicdiseases or pathological conditions, which conditions have animmunologic component, using a compound selected from compounds (A) to(AL) listed below. Such compounds are already known as kinase inhibitorsfor therapy in oncology.

BACKGROUND OF THE INVENTION

[0002] Compounds (A) to (AL) listed below, their preparation as well asthe pharmacological activity of these compounds based on inhibition ofkinases, e.g., VEGFR-2, suitable for therapy in oncology, are disclosedin WO 02/36564, WO 99/52869, WO 00/18734, WO 00/73297, WO 01/27080, WO01/27081 and WO 01/32651. The cited documents are herewith incorporatedby reference.

[0003] Lck, a further tyrosine kinase belonging to the src family oftyrosine kinases not mentioned in the references cited above, isfunctionally required for T-cell activation through the T-cell antigenreceptor (TCR) (see A. E. Nel: T-cell activation through antigenreceptor. Part 1: Signaling components, signaling pathways, and signalintegration at the T-cell antigen receptor synapse. J. Allergy ClinImmunol, 109, 5, 758-770, 2002) and possibly T-cell survival (Seddon,B.; Legname, G.; Tomlinson, P.; Zamoyska, R. : Long-term survival butimpaired homeostatic proliferation of naive T cells in the absence ofp56(lck). Science 290: 127-131, 2000). Therefore, any Lck inhibitor hasa high possible therapeutic potential in the treatment of T-cellmediated diseases, e.q., in the treatment of immunologic diseases.Certain autoimmune diseases such as inflammatory diseases (for example,inflammatory bowel disease, rheumatoid arthritis, glomerulonephritis andlung fibrosis, psoriasis, hypersensitivity reactions of the skin,atherosclerosis, restenosis, allergic asthma, multiple sclerosis andtype 1 diabetes) are believed to be associated with inappropriate T cellactivation (J. H. Hanke et al., Inflamm. Res., 1995, 357). In addition,the acute rejection of transplanted organs as well as Graft versus HostDisease (GvHD) after allogeneic bone marrow and stem celltransplantation can also be interpreted as a consequence ofinappropriate T cell activation. Lck inhibitors offer an approach fortreatment of the indications mentioned hereinbefore. Agents of this kindwould offer therapy for transplant rejection and autoimmune diseaseswhilst avoiding toxicities associated with the commonly used, lessselective immunosuppressants. The leading agent for prevention ortreatment of transplant rejection is cyclosporin A which, althougheffective, is often associated with side-effects such as renal damageand hypertension, which results in kidney failure in a substantialnumber of patients. It is contemporary practice to treat rheumatoidarthritis initially with symptom relief agents such as NSAIDs, whichhave no effect on disease progression and are often associated withunwanted side-effects. A rationally based, disease modifying agent,without such deleterious side-effects, would therefore offer significantbenefits in the prevention or treatment of transplant rejection orautoimmune conditions such as rheumatoid arthritis.

[0004] There is considerable evidence that VEGF plays a key role in thepathogegenesis in rheumatoid arthritis, especially in the formation ofthe pannus (Paleolog E M, Arthritis Res 2002;4 Suppl 3:S81-90, Pavonenet al, J Rheumatol 2002 January;29(1):39-45, Afuwape A O et al, HistolHistopathol 2002;17(3):961-72). Thus, combined inhibition ofVEGFR-tyrosine kinases and Lck is considered of potentially high benefitfor patients with this disease. The same considerations can be appliedto psoriasis and inflammatory bowel disease (Folkman J, Nat Med. 1995January;1(1):27-31. Review; Griga T et al, Hepatogastroenterology 2002January-February; 49(43):116-23, Creamer D et al, Arch Dermatol 2002June; 138(6):791-6).

BRIEF SUMMARY OF THE INVENTION

[0005] In view of the work cited above, there is a clear need forcompounds which are Lck inhibitors for the treatment of T-cell mediateddiseases, e.q., in the treatment of immunologic diseases or pathologicalconditions involving an immunologic component.

[0006] It is therefore an object of the invention to provide a methodfor treating immunologic diseases, or pathological conditions involvingan immunologic component, comprising administering to a patient in needof such treatment an effective amount of a pharmaceutical compositioncomprising a compound selected from compounds (A) to (AL), whichcoumpounds are already known as agents usefully in oncology.

[0007] A second object of the invention is a pharmaceutical compositioncomprising a compound selected from compounds (A) to (AL) together withone or more other drugs selected from nonsteroidal anti-inflammatorydrugs (NSAIDs), steroids, disease-modifying antirheumatic drugs(DMARDs), immunsuppressives, biologic response modifiers andantinfectives for use in treatment of immunologic diseases orpathological conditions involving an immunologic component.

[0008] A third object of the invention is the use of a compound selectedfrom compounds (A) to (AL) for the manufacture of a pharmaceuticalcomposition for the treatment of immunologic diseases or pathologicalconditions involving an immunologic component.

DETAILED DESCRIPTION OF THE INVENTION

[0009] It has now surprisingly been found that compounds

[0010] (A)(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(methylsulfonylamino)-2-indolinone;

[0011] (B)(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone;

[0012] (C) (Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-l-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone;

[0013] (D)(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(phenylsulfonylamino)-2-indolinone;

[0014] (E)(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(4-amino-phenylsulfonylamino)-2-indolinone;

[0015] (F)(Z)-3-(1-(4-(pyrrolidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone;

[0016] (G)(Z)-3-(1-(4-(4-(3-aminopropyl-piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone;

[0017] (H)(Z)-3-(1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene)-5-(phenylsulfonylamino)-2-indolinone;

[0018] (I) (Z)-3-(1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulfonyl-amino)-phenyl-amino)-1-phenyl-methylene)-5-(N-methyl-N-phenylsulfonyl-amino)-2-indolinone;

[0019] (J)(Z)-3-(1-(4-(N-methyl-N-(piperidin-1-yl-methylcarbonyl)-amino)-phenylamino)-1-phenyl-methylene)-5-(N-methyl-N-phenylsulfonyl-amino)-2-indolinone;

[0020] (K) (Z)-3-(1-(2-benzimidazolyl-amino)-1-phenyl-methylene)-5-amido-2-indolinone;

[0021] (L)(Z)-3-(1-(4-(N-methyl-propionylamino)-phenylamino)-1-phenyl-methylene)-5-amido-2-indolinone;

[0022] (M)(Z)-3-(1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulfonyl-amino)-phenyl-amino)-1-phenyl-methylene)-2-indolinone;

[0023] (N)(Z)-3-(1-(4-(N-(3-dimethylaminopropyl)-N-propionyl-amino)-phenylamino)-1-phenyl-methylene)-2-indolinone;

[0024] (O)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(butylcarbamoyl)-2-indolinone;

[0025] (P)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(naphth-1-yl-methyl-carbamoyl)-2-indolinone;

[0026] (Q)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(N-butyl-N-phenyl-carbamoyl)-2-indolinone;

[0027] (R)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(hexylcarbamoyl)-2-indolinone;

[0028] (S)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone;

[0029] (T)(Z)-3-(1-(4-(N-methylsulfonyl-N-(2-dimethylamino-ethyl)-amino)-phenylamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone;

[0030] (U)(Z)-3-(1-(4-(butylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclo-hexylmethyl-carbamoyl)-2-indolinone;

[0031] (V) (Z)-3-(1-(4-(pyrrolidin-1-yl-methyl)-phenylamino)-l-phenyl-methylen )-5-(cyclohexylmethyl-carbamoyl)-2-indolinone;

[0032] (W)(Z)-3-(1-(4-(diethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclo-hexylmethyl-carbamoyl)-2-indolinone;

[0033] (X)(Z)-3-(1-(4-(diethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone;

[0034] (Y)(Z)-3-(1-(4-(diethanolaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(butylcarbamoyl)-2-indolinone;

[0035] (Z)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone;

[0036] (AA)(Z)-3-(1-(4-(N-acetyl-N-(2-dimethylamino-ethyl)-amino)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone;

[0037] (AB)(Z)-3-(1-(4-(butylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone;

[0038] (AC) (Z)-3-(1-(4-(piperidin-1-yl-methyl )-phenylamino)-l-phenyl-methylene)-5-(N-methyl-N-phenyl-aminosulfonyl)-2-indolinone;

[0039] (AD)(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(N-butyl-N-methyl-aminosulfonyl)-2-indolinone;

[0040] (AE)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;

[0041] (AF)(Z)-3-(1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;

[0042] (AG)(Z)-3-(1-(4-(ethylaminomethyl)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;

[0043] (AH)(Z)-3-(1-(4-(1-methyl-imidazol-2-yl)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;

[0044] (AI)(Z)-3-(1-(4-(N-(dimethylaminomethylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;

[0045] (AJ)(Z)-3-(1-(4-(methylaminomethyl)-anilino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;

[0046] (AK)(Z)-3-(1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone;and

[0047] (AL)4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-quinazoline,

[0048] the tautomers, the stereoisomers and the physiologicallyacceptable salts thereof, are effective inhibitors of Lck and thereforeare especially suitable and effective in the treatment of immunologicdiseases or pathological conditions involving an immunologic component.

[0049] Compounds (A) to (J) are described in WO 02/36564, compounds (K)to (L) are described in WO 99/52869, compounds (M) to (N) are describedin WO 00/18734, compounds (0) to (AB) are described in WO 00/73297,compounds (AC) to (AD) are described in WO 01/27080, compounds (AE) to(AK) are described in WO 01/27081, and compound (AL) is described in WO01/32651.

[0050] Viewed from a first aspect, the present invention provides amethod for treating immunologic diseases or pathological conditionsinvolving an immunologic component comprising administering to a patientin need of such treatment an effective amount of a pharmaceuticalcomposition comprising a compound selected from compounds (A) to (AL),the tautomers, the stereoisomers and the physiologically acceptablesalts thereof, optionally in combination with one or more other drugsselected from NSAIDs, steroids, DMARDs, immunsuppressives, biologicresponse modifiers and antinfectives.

[0051] The expression “patient” is meant to comprise the human and thenon-human mammal patient.

[0052] The indication “immunologic diseases or pathological conditionsinvolving an immunologic component” should be understood in anon-limiting manner to comprise:

[0053] autoimmune diseases, for instance inflammatory diseases having anautoimmune component such as inflammatory diseases selected from

[0054] inflammatory bowel disease (e.q., colitis ulcerosa and MorbusCrohn), rheumatoid arthritis, glomerulonephritis and lung fibrosis,

[0055] furthermore, psoriasis, psoriasis arthritis, hypersensitivityreactions of the skin, atherosclerosis, restenosis, asthma, multiplesclerosis and type 1 diabetes, and indications which needimmunosuppressant therapy, for instance prevention or therapy of tissueor organ transplant rejection, e.g., acute or chronic graft-versus-hostdisease, allograft o r x enograft rejection etc. (the transplanted organbeing kidney, heart, liver, lung, bone marrow, peripheral blood stemcells, pancreas or islet cells thereof, cornea, small bowel, skin, orheart valve).

[0056] Preferred indications which may be treated by the methodaccording to the invention are

[0057] rheumatoid arthritis,

[0058] inflammatory bowel disease such as colitis ulcerosa and MorbusCrohn, psoriasis, psoriasis arthritis,

[0059] prevention or therapy of tissue or organ transplant rejection,acute or chronic graft-versus-host disease, allograft or xenograftrejection, and

[0060] allergic asthma, multiple sclerosis and type 1 diabetes.

[0061] A further subgroup of indications which may be treated by themethod according to the invention, and deserves special mention,comprises morbus crohn, lung fibrosis, psoriasis arthritis,hypersensitivity reactions of the skin, graft-versus-host disease (acuteand chronic), asthma, multiple sclerosis and type 1 diabetes.

[0062] A preferred embodiment of the method according to the inventioncomprises administration of a compound selected from compounds

[0063] (A), (B), (C), (D), (F), (G), (P), (T), (V), (X), (Z), (AA),(AE), (AI), (AK) and (AL),

[0064] the tautomers, the stereoisomers and the physiologicallyacceptable salts thereof, optionally in combination with one or moreother drugs selected from NSAIDs, steroids, DMARDs, immunsuppressives,biologic response modifiers and antinfectives.

[0065] Another preferred embodiment of the method according to theinvention comprises administration of a compound selected from thefollowing combined inhibitors of VEGFR-2 and Lck:

[0066] (M), (N), (O), (S), (T), (U), (V), (W), (X), (Y), (Z), (AA),(AB), (AE), (AF), (AG), (AH), (AI), (AJ), (AK) and (AL),

[0067] the tautomers, the stereoisomers and the physiologicallyacceptable salts thereof, optionally in combination with one or moreother drugs selected from NSAIDs, steroids, DMARDs, immunsuppressives,biologic response modifiers and antinfectives. Since VEGF also plays animportant pathogenetical role in chronic inflammatory bowel diseasessuch as colitis ulcerosa and morbus crohn as well as in rheumatoidarthritis, psoriasis and psoriasis arthritis, these combined inhibitorsof VEGFR-2 and Lck are of special advantage in these most preferredindications.

[0068] A further preferred embodiment of the method according to theinvention comprises administration of a compound selected from compounds

[0069] (AK), (AI) and (AL),

[0070] the tautomers, the stereoisomers and the physiologicallyacceptable salts thereof,

[0071] Especially preferred is administration of compound (AK).

[0072] In the method of treatment according to the invention compounds(A) to (AL) can be administered orally, parenterally, rectally or, withrespect to indications involving treatment of the skin (such aspsoriasis, psoriasis arthritis or hypersensitivity reactions of theskin), also in topical formulations. Oral administration is preferred.

[0073] In oral, rectal or topical administration, the compounds may begiven, if required, in divided doses, in a daily dosage of 0.1 to 20mg/kg body weight, preferably 0.5 to 20 mg/kg body weight, mostpreferred 1 to 10 mg/kg body weight. Parenterally, the compounds may beadministered in lower doses, for instance in a total daily dosage of0.01 to 5 mg/kg body weight, preferably 0.05 to 2 mg/kg body weight,most preferred 0.1 to 1 mg/kg body weight.

[0074] For administration, the compounds may be formulated with one ormore conventional inert carriers and/or diluents as known in the art,e.g., with corn starch, lactose, glucose, microcrystalline cellulose,magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid,water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene glycol, stearyl alcohol, carb-oxymethylcellulose orfatty substances such as hard fat or suitable mixtures thereof, inconventional galenic preparations such as plain or coated tablets,lozenges, hard or soft capsules, dispersible powders or granules, syrupsor elixirs, injectable solutions, ampoules, aqueous or oily suspensions,emulsions, solutions, sprays, creams, ointments, gels, or suppositories.Suitable galenic formulations are disclosed in the documents citedhereinbefore.

[0075] Furthermore, in the method according to the invention a compoundselected from compounds (A) to (AL) may be administered in combination,simultaneously or sequentially, with one or more other drugs selectedfrom NSAIDs, steroids, DMARDs, immunsuppressives, biologic responsemodifiers, antinfectives and, in case of lung indications, also withbronchodilators.

[0076] In particular, a compound selected from compounds (A) to (AL)could be used in combination with immunosuppressives in the preventionor treatment of the acute rejection of transplanted organs, incombination with NSAIDs, steroids, immuno-supressives, DMARDs, biologicresponse modifiers (e.q., anti-TNF), and anti-infectives for thetreatment of inflammatory bowel disease (e.q., colitis ulcerosa andmorbus crohn), rheumatoid arthritis and psoriasis, whereby theNSAID-dose can be significantly reduced compared to what otherwise wouldbe required or needed to produce a therapeutic effect. Thus, there wouldbe a reduction in the risk of adverse side-effects from the NSAID, suchas gastrointestinal effects.

[0077] Such compound selected from (A) to (AL) can also be used incombination with biologic response modifiers (e.q., leukotrieneantagonists), and bronchodilators for the treatment of asthma.

[0078] Suitable NSAIDs for combination treatment are meant to includeall COX (cyclooxygenase) inhibitors, e.g.,

[0079] non-selective COX-inhibitors such as acetylsalicyclic acid,mesalazin,

[0080] ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen,ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen,miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid,fluprofen,

[0081] indomethacin, sulindac, tolmetin, zomepirac, nabumetone,diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac, aceclofenac,acemetacin, fentiazac, clidanac, etodolac, oxpinac,

[0082] mefenamic acid, meclofenamic acid, flufenamic acid, nifluminicacid, tolfenamic acid, diflunisal, flufenisal, piroxicam, tenoxicam,lornoxicam and nimesulide and the pharmaceutically acceptable saltsthereof,

[0083] as well as selective COX 2-inhibitors such as meloxicam,celecoxib and rofecoxib and the pharmaceutically acceptable saltsthereof.

[0084] Suitable steroids for combination treatment are meant to includein a non-limiting manner prednisone, prednisolone, methylprednisolone,dexamethasone, budenoside, fluocortolone and triamcinolone.

[0085] Suitable DMARDs for combination treatment are meant to include ina non-limiting manner sulfasalazine, olsalazine, chloroquin, goldderivatives (Auranofin), D-penicillamine and cytostatics such asmethotrexate and cyclophosphamide.

[0086] Suitable immunsuppressives for combination treatment are meant toinclude in a non-limiting manner cyclosporin A and derivatives thereof,mycophenolatemofetil, FK 506, OKT-3, ATG, 15-desoxyspergualin,mizoribine, misoprostol, rapamycin, reflunomide, azathioprine andNF-Kappa B-inhibitors.

[0087] Suitable biologic response modifiers for combination treatmentare meant to include in a non-limiting manner interferon beta,anti-TNF-alpha (Etanercept), IL-10, oral and parenteral toleranceinduction strategies (orally e.q., with genetically modified entericbacteria), leukotrien-antagonists, anti-CD3 or anti-CD25.

[0088] Suitable antinfectives for combination treatment are meant toinclude in a non-limiting manner metronidazol and chinolone fortreatment of chronic inflammatory bowel diseases.

[0089] Suitable bronchodilators for combination treatment are meant toinclude in a non-limiting manner those disclosed under“broncholytics/antiasthmatics” in Rote Liste® 2002, Editio Cantor VerlagAulendorf, Germany, being herewith incorporated by reference, forinstance ipratropium bromide, oxitropium bromide, tiotropium bromide,epinephrine hydrochloride, salbutamole, terbutaline sulfate, fenoterolhydrobromide, salmeterol, formoterol, cromiclinic acid, theophyllinederivatives etc.

[0090] In such combinations each active ingredient can be administeredeither in accordance with its usual dosage range or a dose below itsusual dosage range. The dosage for the combined NSAIDs, steroids,DMARDs, immunsuppressives, biologic response modifiers and antinfectives is appropriately {fraction (1/50)} of the lowest dosenormally recommended up to 1/1 of the normally recommended dosage,preferably {fraction (1/20)} to ½ and more preferably {fraction (1/10)}to {fraction (1/5.)} The normally recommended dose for the combined drugshould be understood to be the dose disclosed for example in Rote Liste®2002, Editio Cantor Verlag Aulendorf, Germany, or in Physician's DeskReference.

[0091] It can be expected that combination treatment comprisingadministration of Lck inhibitors together with a second drug selectedfrom those mentioned hereinbefore may provide synergistic efficacy, thusproviding significant dose reduction compared to what would normally berequired or necessary to produce a therapeutic effect. This would beespecially beneficial with regard to medications having a high risk ofadverse side-effects, as is the case with non-selective COX inhibitors,cyclosporin A or DMARDs.

[0092] Viewed from a second aspect, the present invention also relatesto pharmaceutical compositions comprising

[0093] (a) a compound selected from compounds (A) to (AL), thetautomers, the stereoisomers and the physiologically acceptable saltsthereof,

[0094] (b) and one or more other drugs selected from NSAIDs, steroids,DMARDs, immunsuppressives, biologic response modifiers andantinfectives,

[0095] optionally together with pharmaceutically acceptable diluentsand/or carriers, as a combined preparation or a kit of parts containingcomponents (a) and (b) in separate containments for simultaneous,separate or sequential use in treatment of immunologic diseases orpathological conditions involving an immunologic component.

[0096] Viewed from a third aspect, the present invention provides theuse of a compound selected from compounds (A) to (AL), the tautomers,the stereoisomers and the physiologically acceptable salts thereof,optionally in combination with one or more other drugs selected fromNSAIDs, steroids, DMARDs, immunsuppressives, biologic response modifiersand antinfectives, for the manufacture of a pharmaceutical compositionfor the treatment of a patient suffering from immunologic diseases orpathological conditions involving an immunologic component.

[0097] Preferred embodiments of either the composition aspect or the useaspect of the invention with respect tot he combined VEGFR-2/Lckcomponent correspond to those mentioned hereinbefore for the method oftreatment aspect.

EXAMPLE 1 Non-Radioactive Kinase Assay (lck)

[0098] Methodology

[0099] The lck enzyme comprises the entire lck molecule except the firstnine amino acids which are replaced by an His-tag for purificationpurposes. The enzyme is affinity purified.

[0100] The assay mix is assembled in a well of a 96-well round bottommicrotiter plate and contains 10 μl PBS (either as such or with aninhibitor dissolved at an appropriate concentration), 20 μl substratesolution (200 mM Hepes, pH=7,4; 50 mM MgAc₂; 1 mM Na₃VO₄;250 μg/mlpoly-Glu-Tyr (Sigma P0275); 200 ng/ml biotinylated peptide(biot-Ala-Glu-Glu-Glu-lle-Tyr-Gly-Glu-Phe-Glu-Ala-Lys-Lys-Lys-Lys) and20 μl of 2.5 ng/μl enzyme (diluted from affinity purified stock withenzyme dilution buffer, EDB:20 mM Hepes, pH=7.4, 130 mM NaCl, 0.05%Triton X-100).

[0101] The reaction is started by the addition of 50 μl 500 μM ATP (in10 mM MgAc₂) and is performed at room temperature. After 30 minutes 50μl stop solution (20 mM Hepes, pH=7.4;250 mM EDTA) are added and 100 μlof this solution transfered to the well of a streptavidin coatedmicrotiter plate (SA-MTP, Boehringer Mannheim, #1664-760).

[0102] The solution is incubated for one hour at room temparature andthe supernatant discarded. The well is washed twice with 300 μl, PBS.

[0103] The streptavidin bound biotinylated peptide is incubated for 1hour at room temperature with 100 μl Eu³⁺-labelled anti-phosphotyrosineantibody solution (0.3 mg/ml DELFIA-Eu-labelled PT66 (Wallac, AD0041);50 mM Tris, pH=7.8; 0.05% Tween 20; 0.5% (w7v) BSA (Serva, diagnosticgrade) under gentle agitation. The well is washed three times with 1×Delfia wash buffer (Wallac, 1244-114, 25× concentrate, diluted withwater) and finally 100 μl Delfia enhancement solution (Wallac, 1244-105)are added.

[0104] Time resolved fluorescense is measured in a Wallac Victor2 1420Multilabel Counter, excitation is at 340 nm, emission is measured at 615nm (delay time 400 μsec, window time 1000 μsec).

[0105] Results

[0106] In two independent experiments the lC₅₀s of compounds (A) to (AL)on the kinase have been determined. The data (mean values) obtained withthree representative compounds are summarised in the following table:compound Lck; IC₅₀ [nM] (AK) 16 (AI) 36 (AL) 58

[0107] Compounds (A) to (AH) and (AJ) inhibit the lck kinase functionwith an lC₅₀<1 μM.

What is claimed is:
 1. A method for treating immunologic diseases orpathological conditions involving an immunologic component comprisingadministering to a patient in need of such treatment an effective amountof a pharmaceutical composition comprising a compound selected from (A)(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(methylsulfonylamino)-2-indolinone;(B)(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone;(C)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone;(D)(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(phenylsulfonylamino)-2-indolinone;(E)(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(4-amino-phenylsulfonylamino)-2-indolinone;(F)(Z)-3-(1-(4-(pyrrolidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone;(G)(Z)-3-(1-(4-(4-(3-aminopropyl-piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone;(H)(Z)-3-(1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene)-5-(phenylsulfonylamino)-2-indolinone;(I)(Z)-3-(1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulfonyl-amino)-phenyl-amino)-1-phenyl-methylene)-5-(N-methyl-N-phenylsulfonyl-amino)-2-indolinone;(J)(Z)-3-(1-(4-(N-methyl-N-(piperidin-1-yl-methylcarbonyl)-amino)-phenylamino)-1-phenyl-methylene)-5-(N-methyl-N-phenylsulfonyl-amino)-2-indolinone;(K)(Z)-3-(1-(2-benzimidazolyl-amino)-1-phenyl-methylene)-5-amido-2-indolinone;(L)(Z)-3-(1-(4-(N-methyl-propionylamino)-phenylamino)-1-phenyl-methylene)-5-amido-2-indolinone;(M) (Z)-3-(1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulfonyl-amino)-phenyl-amino)-1-phenyl-methylene)-2-indolinone;(N)(Z)-3-(1-(4-(N-(3-dimethylaminopropyl)-N-propionyl-amino)-phenylamino)-1-phenyl-methylene)-2-indolinone;(O)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(butylcarbamoyl)-2-indolinone;(P)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(naphth-1-yl-methyl-carbamoyl)-2-indolinone;(Q)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(N-butyl-N-phenyl-carbamoyl)-2-indolinone;(R)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(hexylcarbamoyl)-2-indolinone;(S)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone;(T)(Z)-3-(1-(4-(N-methylsulfonyl-N-(2-dimethylamino-ethyl)-amino)-phenylamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone; (U)(Z)-3-(1-(4-(butylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclo-hexylmethyl-carbamoyl)-2-indolinone;(V) (Z)-3-(1-(4-(pyrrolidin-1-yl-methyl)-phenylamino)-1-phenyl-methylen)-5-cyclohexylmethyl-carbamoyl)-2-indolinone; (W)(Z)-3-(1-(4-(diethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclo-hexylmethyl-carbamoyl)-2-indolinone;(X)(Z)-3-(1-(4-(diethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone;(Y)(Z)-3-(1-(4-(diethanolaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(butylcarbamoyl)-2-indolinone;(Z)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone; (AA)(Z)-3-(1-(4-(N-acetyl-N-(2-dimethylamino-ethyl)-amino)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone; (AB)(Z)-3-(1-(4-(butylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone;(AC)(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(N-methyl-N-phenyl-aminosulfonyl)-2-indolinone;(AD) (Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(N-butyl-N-methyl-aminosulfonyl)-2-indolinone;(AE)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;(AF)(Z)-3-(1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;(AG)(Z)-3-(1-(4-(ethylaminomethyl)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;(AH)(Z)-3-(1-(4-(1-methyl-imidazol-2-yl)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;(AI)(Z)-3-(1-(4-(N-(dimethylaminomethylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;(AJ)(Z)-3-(1-(4-(methylaminomethyl)-anilino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;(AK)(Z)-3-(1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone;and (AL)4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-quinazolinethe tautomers, the stereoisomers and the physiologically acceptablesalts thereof, or a combination of any of the above.
 2. The method ofclaim 1, wherein the pharmaceutical composition further comprises one ormore other drugs selected from nonsteroidal anti-inflammatory drugs(NSAIDs), steroids, disease-modifying antirheumatic drugs (DMARDs),immunsuppressives, biologic response modifiers, antinfectives, andcombinations of any of the above.
 3. The method of claim 1, wherein theimmunologic disease or pathological condition involving an immunologiccomponent is selected from autoimmune diseases, for instanceinflammatory diseases having an autoimmune component such asinflammatory diseases selected from inflammatory bowel disease (e.q.,colitis ulcerosa and Morbus Crohn), rheumatoid arthritis,glomerulonephritisand lung fibrosis, furthermore, psoriasis, psoriasisarthritis, hypersensitivity reactions of the skin, atherosclerosis,restenosis, asthma, multiple sclerosis and type 1 diabetes, andindications which need immunosuppressant therapy, for instanceprevention or therapy of tissue or organ transplant rejection.
 4. Themethod of claim 3, wherein the immunologic disease or pathologicalcondition involving an immunologic component is selected from rheumatoidarthritis, inflammatory bowel disease such as colitis ulcerosa andMorbus Crohn, psoriasis, psoriasis arthritis, prevention or therapy oftissue or organ transplant rejection, acute or chronic graft-versus-hostdisease, allograft or xenograft rejection, allergic asthma, multiplesclerosis and type 1 diabetes.
 5. The method of claim 3, wherein theimmunologic disease or pathological condition involving an immunologiccomponent is selected from morbus crohn, lung fibrosis, psoriasisarthritis, hypersensitivity reactions of the skin, graft-versus-hostdisease (acute and chronic), asthma, multiple sclerosis and type 1diabetes.
 6. The method of claim 3, wherein the immunologic disease orpathological condition involving an immunologic component is selectedfrom chronic inflammatory bowel diseases, such as colitis ulcerosa andmorbus crohn, from rheumatoid arthritis, psoriasis and psoriasisarthritis.
 7. The method according to claim 1, which method comprisesadministration of a pharmaceutical composition comprising (A), (B), (C),(D), (F), (G), (P), (T), (V), (X), (Z), (AA), (AE), (AI), (AK), and (AL)the tautomers, the stereoisomers and the physiologically acceptablesalts thereof, or a combination of any of the above.
 8. The method ofclaim 6, which method comprises administration of a compound selectedfrom (M), (N), (O), (S), (T), (U), (V), (W), (X), (Y), (Z), (AA), (AB),(AE), (AF), (AG), (AH), (AI), (AJ), (AK) and (AL), the tautomers, thestereoisomers and the physiologically acceptable salts thereof, or acombination of any of the above.
 9. The method according to claim 1,which method comprises administration of a pharmaceutical compositioncomprising from (AK), (AI) and (AL) the tautomers, the stereoisomers andthe physiologically acceptable salts thereof.
 10. The method accordingto claim 1, wherein the pharmaceutical composition is administeredorally, parenterally, rectally or, with respect to indications involvingtreatment of the skin such as psoriasis, psoriasis arthritis orhypersensitivity reactions of the skin, also topically.
 11. Apharmaceutical composition comprising (i) a compound selected from: (A)(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(methylsulfonylamino)-2-indolinone;(B)(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone;(C) (Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone;(D)(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(phenylsulfonylamino)-2-indolinone;(E)(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(4-amino-phenylsulfonylamino)-2-indolinone;(F) (Z)-3-(1-(4-(pyrrolidin-1-yl-methyl)-phenylamino)-l-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone; (G)(Z)-3-(1-(4-(4-(3-aminopropyl-piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone;(H)(Z)-3-(1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene)-5-(phenylsulfonylamino)-2-indolinone;(I) (Z)-3-(1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulfonyl-amino)-phenyl-amino)-1-phenyl-methylene)-5-(N-methyl-N-phenylsulfonyl-amino)-2-indolinone;(J)(Z)-3-(1-(4-(N-methyl-N-(piperidin-1-yl-methylcarbonyl)-amino)-phenylamino)-1-phenyl-methylene)-5-(N-methyl-N-phenylsulfonyl-amino)-2-indolinone;(K)(Z)-3-(1-(2-benzimidazolyl-amino)-1-phenyl-methylene)-5-amido-2-indolinone;(L)(Z)-3-(1-(4-(N-methyl-propionylamino)-phenylamino)-1-phenyl-methylene)-5-amido-2-indolinone;(M)(Z)-3-(1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulfonyl-amino)-phenyl-amino)-1-phenyl-methylene)-2-indolinone;(N)(Z)-3-(1-(4-(N-(3-dimethylaminopropyl)-N-propionyl-amino)-phenylamino)-1-phenyl-methylene)-2-indolinone;(O)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(butylcarbamoyl)-2-indolinone;(P)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(naphth-1-yl-methyl-carbamoyl)-2-indolinone;(Q)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(N-butyl-N-phenyl-carbamoyl)-2-indolinone;(R)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(hexylcarbamoyl)-2-indolinone;(S)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone;(T)(Z)-3-(1-(4-(N-methylsulfonyl-N-(2-dimethylamino-ethyl)-amino)-phenylamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone;(U)(Z)-3-(1-(4-(butylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclo-hexylmethyl-carbamoyl)-2-indolinone;(V) (Z)-3-(1-(4-(pyrrolidin-1-yl-methyl)-phenylamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone; (W)(Z)-3-(1-(4-(diethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclo-hexylmethyl-carbamoyl)-2-indolinone;(X)(Z)-3-(1-(4-(diethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone;(Y)(Z)-3-(1-(4-(diethanolaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(butylcarbamoyl)-2-indolinone;(Z)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl )-2-indolinone; (AA)(Z)-3-(1-(4-(N-acetyl-N-(2-dimethylamino-ethyl)-amino)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl )-carbamoyl)-2-indolinone; (AB)(Z)-3-(1-(4-(butylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone;(AC) (Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(N-methyl-N-phenyl-aminosulfonyl)-2-indolinone;(AD)(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(N-butyl-N-methyl-aminosulfonyl)-2-indolinone;(AE)(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;(AF)(Z)-3-(1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;(AG)(Z)-3-(1-(4-(ethylaminomethyl)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;(AH)(Z)-3-(1-(4-(1-methyl-imidazol-2-yl)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;(AI)(Z)-3-(1-(4-(N-(dimethylaminomethylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;(AJ)(Z)-3-(1-(4-(methylaminomethyl)-anilino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;(AK)(Z)-3-(1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone;and (AL)4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-quinazolinethe tautomers, the stereoisomers and the physiologically acceptablesalts thereof, or a combination of any of the above (b) one or moreother drugs selected from NSAIDs, steroids, DMARDs, immunsuppressives,biologic response modifiers and antinfectives.
 12. The pharmaceuticalcomposition according to claim 11 further comprising one or morepharmaceutically acceptable diluents and/or carriers.
 13. Thecomposition of claim 11, wherein the NSAID is a non-selectiveCOX-inhibitor or a COX-2 selective inhibitor.
 14. The composition ofclaim 11, wherein the NSAID is selected from acetylsalicyclic acid,mesalazin, ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen,ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen,miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid,fluprofen, indomethacin, sulindac, tolmetin, zomepirac, nabumetone,diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac, aceclofenac,acemetacin, fentiazac, clidanac, etodolac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, nifluminic acid, tolfenamic acid,diflunisal, flufenisal, piroxicam, tenoxicam, lornoxicam, nimesulide,meloxicam, celecoxib and rofecoxib, and the pharmaceutically acceptablesalts thereof.
 15. The composition of claim 11, wherein the steroid isselected from prednisone, prednisolone, methylprednisolone,dexamethasone, budenoside, fluocortolone and triamcinolone.
 16. Thecomposition of claim 11, wherein the DMARD is selected fromsulfasalazine, olsalazine, chloroquin, gold derivatives (Auranofin),D-penicillamine and cytostatics such as methotrexate andcyclophosphamide.
 17. The composition of claim 11, wherein theimmunsuppressive is selected from cyclosporin A and derivatives thereof,mycophenolatemofetil, FK 506, OKT-3, ATG, 15-desoxyspergualin,mizoribine, misoprostol, rapamycin, reflunomide, azathioprine andNF-Kappa B-inhibitors.
 18. The composition of claim 11, wherein thebiologic response modifier is selected from interferon beta,anti-TNF-alpha (Etanercept), IL-10, oral and parenteral toleranceinduction strategies, leukotrien-antagonists, anti-CD3 and anti-CD25.19. The composition of claim 11, wherein the biologic response modifieris a bronchodilator selected from ipratropium bromide, oxitropiumbromide, tiotropium bromide, epinephrine hydrochloride, salbutamol,terbutaline sulphate, fenoterol hydrobromide, salmeterol, formoterol,cromiclinic acid, a theophylline derivative and a combination of any ofthe above.
 20. The composition of claim 11, wherein the antinfective isselected from metronidazol and chinolone.